Diagnosing malabsorption with systemic lipid ... - Semantic Scholar

1 downloads 0 Views 510KB Size Report
Jun 18, 2012 - Abstract. Objective: A Malabsorption. Blood Test (MBT) is proposed as an alterna- tive method to the 72-hour stool and dietary collection for ...
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 4/2013 (263-273)

Original ©2013 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965 DOI 10.5414/CP201793 e-pub: January 29, 2013

Diagnosing malabsorption with systemic lipid profiling: pharmacokinetics of pentadecanoic acid and triheptadecanoic acid following oral administration in healthy subjects and subjects with cystic fibrosis Virginia A. Stallings1,2, John T. Mondick3*, Joan I. Schall1, Jeffrey S. Barrett2,3, Martha Wilson4 and Maria R. Mascarenhas1,2 1Division

of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, 2Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, 3Division of Clinical Pharmacology and Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA and 4Pathology – Lipid Science, Wake Forest School of Medicine, Winston-Salem, NC, USA

Key words dietary fat malabsorption – orlistat – cystic fibrosis – chronic pancreatitis – pentadecanoic acid – triheptadecanoic acid

*current address, Metrum Research Group, Tariffville, CT, USA Received June 18, 2012; accepted November 14, 2012 Correspondence to Virginia A. Stallings, MD Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, 3535 Market St., Rm. 1558, Philadelphia, PA 19104, USA stallingsv@ email.chop.edu

Abstract. Objective: A Malabsorption Blood Test (MBT) is proposed as an alternative method to the 72-hour stool and dietary collection for assessing the degree of fat malabsorption in people with pancreatic insufficiency. The MBT consists of a simultaneous oral dose of pentadecanoic acid (PA), a free fatty acid, and triheptadecanoic acid (THA), a triglyceride with three heptadecanoic (HA) saturated fatty acids requiring hydrolysis by pancreatic lipase before HA can be intestinally absorbed. The aim of this study is to demonstrate the ability of MBT to detect fat malabsorption in healthy adult subjects using the pancreatic lipase (PL) inhibitor Orlistat (Xenical®), and in subjects with CF and PI while on and off routine pancreatic enzyme doses. Materials and methods: The MBT with the PA and THA were delivered in a breakfast test meal (2.5 g PA and either 5 g or 8 g THA) to healthy adult subjects (ages 18 – 50 years, BMI 21 – 30) and to subjects with CF (> 12 years, FEV1% predicted > 40%), after a 12-hour fast and 24 hours without dairy foods. Serum levels of PA and HA were assessed by gas-liquid chromatography, from blood samples drawn prior to MBT and then hourly for 8 hours. For healthy subjects, the MBT was administered before and after Orlistat treatment, and in subjects with CF, both with subjects receiving routine pancreatic lipase treatment (“on enzyme”) and also “off enzyme” treatment. Treatment groups were compared for baseline (C0) and maximum (Cmax) plasma concentrations of PA and HA over 8 hours: area under the curve (AUC) was calculated using linear trapezoid method. The ratio of HA to PA Cmax and AUC was also calculated and

compared. Results: For the healthy subjects (n = 15, 60% female, ages 21 – 49 years), absorption of HA was reduced 71% for Cmax (p  30 kg/m2, diabetes mellitus, or disorders associated with altered energy metabolism or gastrointestinal motility. Subjects who were taking blood lipid lowering drugs were not eligible. The aim of the CF Pharmacokinetics Study was to determine PA and HA pharmacokinetics in subjects with CF and PI with and without their prescribed pancreatic enzyme medication. The baseline MBT doses were 2.5 g of PA and either 5.0 g or 8.0 g of HA on two separate occasions. In random order, the MBT was administered with or without the subject’s normal evening meal dose of pancreatic enzymes. The two MBT tests were performed at least 7 days apart. Patients with CF and PI who were 8 years of age or older and in an otherwise state of good health were enrolled. The diagnosis of CF was based upon clinical symptoms and duplicate quantitative pilocarpine iontophoresis sweat tests with Na and Cl values > 60 mEq/l. PI was determined based on clinical symptoms and laboratory values including 72-hour fecal fat analysis with